The present invention relates to pharmaceutical compositions containing DMSO for adminstration to human or other animal subjects. More specifically, it relates to new DMSO formulations containing substances which enhance the effectiveness of DMSO, reduce undesirable side-effects sometimes created by the use of DMSO and make DMSO compositions more appealing to users.
Dimethyl sulfoxide (DMSO) is a versatile substance that has numerous pharmaceutical and nonpharmaceutical uses. It is widely used throughout the world for treating humans and other animal subjects.
As Described in U.S. Pat. No. 3,549,770, No. 3,740,420, and No. 3,790,682, incorporated herein by the reference, DMSO is an active agent in relieving the signs and symptoms of numerous body disorders, including accelerating the healing of certain injured body tissues and in relieving the signs and symptoms of anxiety.
U.S. Pat. No. 3,551,554, No. 3,711,606 and No. 3,743,727, incorporated herein by reference, describe how DMSO is effective to enhance tissue penetration of other substances, especially other physiologically active agents. DMSO can thus be added to a variety of pharmaceutical compositions to accelerate assimilation into body tissue. In some instances this means that smaller doses can be administered when DMSO is used.
Yet, despite their many benefits, DMSO compositions are sometimes passed over in favor of other pharmaceutical compositions even in instances where DMSO would be the most effective pharmaceutical agent. This is because many subjects suffer from one or more side-effects when treated with DMSO. In some cases, the side-effects are so pronounced that subject or physician will forego the use of DMSO in favor of a less effective therapeutic agent.
A variety of undesirable side-effects have been observed to result from administration of DMSO. The most frequently occurring are adverse skin reactions, malodorous breath and foul taste.
The adverse reactions caused by DMSO are well documented. At page 356 of the standard reference Contact Dermatitis by Alexander A. Fisher, M.D. (2nd Ed., 1973), dimethyl sulfoxide (DMSO) is listed as a primary urticariogen. Volume 141 of Annals New York Academy of Sciences includes several articles describing the undesirable side-effects attributed to DMSO. These include articles by Goldman, et al. at pages 429, 433-35; Sulzberger, et al. at pages 439-40; Brown at pages 500-501; and several others.
The magnitude of the malodorous breath problem is so large that, in some instances, hospitals have had to isolate wards where DMSO is administered from the central air conditioning system. Skin irritations from topically applied DMSO have been so great that a substantial number of patients refuse treatment.
Another, potentially more serious side-effect is sometimes observed when DMSO is administered intravenously. This is red blood cell lysis. Intravenous administration of DMSO is crucial if the substance is to be used for treating the brain and spinal cord, for cancer therapy or to treat organ hypoxia, heart attack and other internal conditions. Large intravenous doses of DMSO can have a therapeutic effect for such purposes but red blood cell lysis which results from intravenous DMSO administration can be injurious or even fatal to the subject.
Furthermore, it is generally advisable to minimize the dosage of any pharmaceutical substance administered to a human or other animal subject to the smallest effective amount. Although DMSO is one of the most penetrating of pharmaceutical substances and is known to be effective in minute doses, it would be desirable to further reduce the minimum dosage of DMSO needed to achieve a desired physiological effect.
A related problem is observed when fish are treated with hyperosmotic concentrations of a membrane permeability altering agent as discussed in U.S. Pat. No. 4,112,946, incorporated herein by reference. Such agents include urea, NaCl and acetamide.
These substances, with the possible exception of acetamide, are substantially nontoxic when applied externally to mammalian subjects. But, when incorporated in a solution in contact with an epithelial membrane of fish, such substances can be lethal at moderate concentrations (as low as about 3 weight percent).
To optimize delivery of therapeutic agents to fish, solutions containing greater than 3 weight percent of the above listed solutes are required. Fish mortality is thus a substantial barrier to the effective use of hyperosmotic treatments.